Emerging evidence is revealing that exosomes contribute to many aspects of physiology and disease through intercellular communication. However, the biological roles of exosome secretion in exosome-secreting cells have remained largely unexplored. Here researchers from the Japanese Foundation for Cancer Research show that exosome secretion plays a crucial role in maintaining cellular homeostasis in exosome-secreting cells. The inhibition of exosome secretion results in the accumulation of nuclear DNA in the cytoplasm, thereby causing the activation of cytoplasmic DNA sensing machinery. This event provokes the innate immune response, leading to reactive oxygen species (ROS)-dependent DNA damage response and thus induce senescence-like cell-cycle arrest or apoptosis in normal human cells. These results, in conjunction with observations that exosomes contain various lengths of chromosomal DNA fragments, indicate that exosome secretion maintains cellular homeostasis by removing harmful cytoplasmic DNA from cells. Together, these findings enhance our understanding of exosome biology, and provide valuable new insights into the control of cellular homeostasis.
A model of exosome-mediated cellular homeostasis
The exosome secretion eliminates harmful cytoplasmic DNA from cells. The inhibition of exosome secretion causes the cytoplasmic accumulation of nuclear DNA, thereby causing the activation of STING, the cytoplasmic DNA sensing machinery. This event provokes the innate immune response, such as type I IFN pathway, leading to the elevation of the intracellular levels of ROS. In turn, this activates the DDR in normal human cells. This machinery may also play keys role in preventing viral hijacking of host cells by excreting viral DNA from cells.